Project Summary/Abstract The age of genomics ushered in unprecedented growth in our understanding of the connection between genotype and phenotype. Yet despite intense interest, we have made comparatively little progress in understanding the contribution of genes to behavior. This is in part due to the complexity of behavior, which involves many genes throughout the genome. Thus, there is a need for an animal model in which causal links can be made between discrete changes in gene sequence and changes in behavior. A new animal model in behavioral genetics is uniquely suited to revealing the connection between genotype and phenotype: the white- throated sparrow (Zonotrichia albicollis). In this species, a chromosomal rearrangement has caused changes in social behavior. Individuals with the rearrangement engage in more territorial aggression than do individuals without it. An identified portion of the genome affecting social behavior in vertebrates is extremely rare, and as such, this species offers an outstanding opportunity to study the mechanisms by which variation in a known set of genes causes variation in social behavior. This rearrangement has led to the accumulation of mutations in a number of genes involved in aggression, including the gene encoding estrogen receptor alpha (ER?). The expression of ER? depends on genotype in multiple regions of the brain of this species. In one of those regions, ER? expression both within and between genotypes strongly predicts territorial aggression. The central hypothesis of this proposal is that individual variation in the ER? gene sequence has caused individual differences in aggressive behavior. The PI will test the hypothesis by 1) identifying the genetic and epigenetic factors likely to contribute to differential expression of ER?, and 2) manipulating the expression of ER? to show that its differential expression in one brain region is causal for the differential aggressive behavior. This project is innovative because it uses an interdisciplinary approach to investigate a gene-behavior connection in a wild animal. The significance of the proposed work is that the PI will use an experimental approach to reveal mechanisms by which social behavior can evolve. The PI has assembled an interdisciplinary team that includes experts in the regulation of hormone receptors, comparative genomics, neuroscience, and behavioral neuroendocrinology; this team is ideal to train the PI in techniques that will allow her to address the central hypothesis of this proposal. This unique project represents an excellent opportunity for the PI train in diverse fields in order to prepare for a career as an independent investigator at a major research university.